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Molecular and Behavioral Neurobiology of Transcription Factor TCF4

转录因子 TCF4 的分子和行为神经生物学

基本信息

批准号：
9104200
负责人：
John David Sweatt
金额：
$ 14.7万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104200
关键词：
Accounting Acetylesterase Acute Address Adult Alleles Anatomy Area Auditory Autistic Disorder BHLH Protein Behavior Behavioral Binding Bioinformatics Boxing Brain Breeding Categories Chromatin Structure Cognition Cognitive Complex Coupled DNA DNA Methylation Dendritic Spines Development Diagnosis Electrophysiology (science)Epigenetic Process Etiology Exhibits Exons Family Gene Targeting Genes Genetic Genetic Engineering Genetic Transcription Genetically Engineered Mouse Genomics Health Hippocampus (Brain)Histone Deacetylase Histone Deacetylase Inhibitor Histones Homo Human Impaired cognition Introns Knock-out Laboratories Language Language Development Learning Long-Term Potentiation LoxP-flanked allele Mediating Memory Memory impairment Messenger RNA Modeling Molecular Molecular Biology Motor Mus Mutation Nervous System Physiology Neuraxis Neurobiology Neurons Patients Pharmacotherapy Physiological Predisposition Prosencephalon Regulation Regulatory Element Resources Role Route Schizophrenia Small RNA Social Behavior Social Interaction Susceptibility Gene Synapses Synaptic plasticity Syndrome TCF7L2 gene Testing Transcriptional Activation Transcriptional Regulation Veins Virus attenuation autistic behaviour base calmodulin-dependent protein kinase II cognitive function epigenomics experience gene function gene product genetic risk factor genome wide association study improved in vivo inhibitor/antagonist innovation knock-down learned behavior loss of function mouse model next generation sequencing novel novel therapeutics overexpression promoter response social communication synaptic function transcription factor transcriptome sequencing transcriptomics

项目摘要

DESCRIPTION (provided by applicant): The basic helix-loop-helix transcription factor TCF4 (aka E2-2) has been implicated broadly in human CNS function. TCF4 was confirmed in several large GWAS studies as one of the rare highly replicated schizophrenia susceptibility genes, and when haplo-insufficient TCF4 is the causative factor for Pitt-Hopkins Syndrome (PTHS). PTHS has compelling attributes in terms of human cognitive function, being associated with pronounced memory deficits, autistic behaviors, and importantly an almost complete lack of language development. Thus, understanding the roles and function of TCF4 in the CNS is highly significant with respect to human language and auditory cognition, memory function, autism spectrum behavior, and schizophrenia susceptibility. Despite the clear importance of TCF4 function in the human CNS, the basic neurobiology of TCF4 has been only sparsely studied. Thus, this Project will use genetically engineered mouse models to assess the role of TCF4 in memory, social interactions and communication, hippocampal synaptic plasticity, synaptic anatomy, and epigenomic and transcriptional regulation in the CNS. The central hypothesis of the proposed studies is that TCF4 regulates the brain's ability to trigger long-term synaptic plasticity and memory formation by actively regulating transcriptional activity in response to behavioral experience. The approach will be to use both germline constitutive knockout and acute knockdown or deletion of TCF4 in the adult mouse hippocampus, coupled with extensive behavioral, electrophysiological, and transcriptomic/epigenomic characterization, to determine if TCF4 function is necessary in an ongoing fashion for normal memory and synaptic plasticity in the mature CNS. The studies will capitalize not only upon the available germline knockout line but also upon an already-available floxed TCF4 allele mouse line, and combine these mice with both virus- driven cre expression in the adult hippocampus and post-developmental CaMKII promoter-driven forebrain neuron-selective cre expression to achieve inducible post-developmental attenuation of CNS TCF4 function in vivo. Using these novel mouse models we will undertake three Specific Aims. Aim 1 will test the hypothesis that TCF4-deficient mice exhibit cognitive memory and social interaction deficits, and also test the hypothesis that TCF4-deficient mice exhibit altered synaptic plasticity. Aim 2 will comprise a significant translational component of the studies and will test the hypothesis that transcription-promoting Histone DeAcetylase Inhibitors (HDACi) will restore learning, memory, and synaptic plasticity in TCF4-deficient mice, as proof-of- concept that behavioral deficits and plasticity deficits in PTHS model mice can be reversed pharmacologically with HDACi. Aim 3 will test the hypothesis that loss of TCF4 function triggers secondary alterations in chromatin structure, DNA methylation, and gene transcription in the mature CNS. Toward this end, we will use the unbiased approach of utilizing MBD-seq, mRNA-seq, and small RNA-seq approaches for a comprehensive analysis of potential transcriptomic and epigenomic alterations in TCF4-deficient mice.

描述（由申请人提供）：碱性螺旋-环-螺旋转录因子TCF 4（又名E2-2）广泛参与人类CNS功能。TCF 4在几项大型GWAS研究中被证实为罕见的高度复制的精神分裂症易感基因之一，并且当TCF 4单倍不足时是Pitt-Hopkins综合征（PTHS）的致病因素。PTHS在人类认知功能方面具有令人信服的属性，与明显的记忆缺陷，自闭症行为以及重要的几乎完全缺乏语言发育有关。因此，了解TCF 4在中枢神经系统中的作用和功能对于人类语言和听觉认知、记忆功能、自闭症谱系行为和精神分裂症易感性具有重要意义。尽管TCF 4在人类CNS中的功能具有明确的重要性，但TCF 4的基础神经生物学研究很少。因此，本项目将使用基因工程小鼠模型来评估TCF 4在记忆、社会互动和交流、海马突触可塑性、突触解剖以及CNS中的表观基因组和转录调控中的作用。提出的研究的中心假设是，TCF 4调节大脑的能力，触发长期突触可塑性和记忆形成的积极调节转录活性，以响应行为经验。该方法将使用两个种系组成性敲除和急性敲除或删除TCF 4在成年小鼠海马，加上广泛的行为，电生理学，和转录组学/表观基因组表征，以确定是否TCF 4功能是必要的，在一个正在进行的方式在成熟的中枢神经系统中的正常记忆和突触可塑性。这些研究将不仅利用可用的种系敲除系，而且利用已经可用的floxed TCF 4等位基因小鼠系，并将这些小鼠与成年海马中病毒驱动的cre表达和发育后CaMKII启动子驱动的前脑神经元选择性cre表达相结合，以实现CNS TCF 4功能的体内诱导性发育后衰减。使用这些新的小鼠模型，我们将进行三个特定的目标。目的1将检验TCF 4缺陷小鼠表现出认知记忆和社会互动缺陷的假设，并检验TCF 4缺陷小鼠表现出突触可塑性改变的假设。目标2将包括一个重要的翻译作为研究的组成部分，将检验促进转录的组蛋白去乙酰化酶抑制剂（HDACi）将恢复TCF 4缺陷小鼠的学习、记忆和突触可塑性的假设，作为PTHS模型中的行为缺陷和可塑性缺陷的概念验证。小鼠可以用HDACi逆转逆转。目的3将检验TCF 4功能丧失引发成熟CNS中染色质结构、DNA甲基化和基因转录的继发性改变的假设。为此，我们将使用MBD-seq，mRNA-seq和小RNA-seq方法的无偏方法，对TCF 4缺陷小鼠中潜在的转录组和表观基因组改变进行全面分析。